Erotomania and phenotypic continuum in a family frameshift variant of AUTS2: a case report and review.

BACKGROUND: Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene. CASE PRESENTATION: The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant. CONCLUSIONS: The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research.

Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study).

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents' sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.

Heparin-induced multiple electrode aggregometry is a promising and useful functional tool for heparin-induced thrombocytopenia diagnosis: confirmation in a prospective study.

Heparin-induced thrombocytopenia (HIT) is a potentially lethal adverse effect of heparin therapy. Accurate and rapid HIT laboratory diagnosis when HIT is suspected is crucial. The combination of an immunological assay with a functional test improves the accuracy of HIT, but functional assays are currently limited to a few laboratories. Multiplate® analyzer (Dynabyte, Munich, Germany) is a practical, semi-automated and easy-to-perform platelet aggregation assay. The aim of this study is to explore whether heparin-induced platelet aggregation in whole blood assessed by Multiplate® (Heparin-induced multiple electrode aggregometry, HIMEA) can replace platelet aggregation test (PAT) in platelet-rich plasma. For this purpose, HIMEA performance in HIT diagnosis was prospectively evaluated. HIMEA and PAT were compared to serotonin-release assay (SRA) in 200 well-characterized consecutive patients suspected for HIT. HIMEA was found to be more sensitive (81% vs. 76%) and more specific (99% vs. 96%) than PAT compared to SRA. Both tests showed a high negative predictive value while HIMEA had a better positive predictive value. HIMEA has overall better performance characteristics than PAT for the detection of HIT platelet-activating antibodies. The combination of an immunological assay with HIMEA could be a feasible option in non-specialized laboratories for HIT diagnosis optimization.

Anxiety, concerns and COVID-19: Cross-country perspectives from families and individuals with neurodevelopmental conditions.

Background: The COVID-19 pandemic had a major impact on the mental health and well-being of children with neurodevelopmental conditions (NDCs) and of their families worldwide. However, there is insufficient evidence to understand how different factors (e.g., individual, family, country, children) have impacted on anxiety levels of families and their children with NDCs developed over time. Methods: We used data from a global survey assessing the experience of 8043 families and their children with NDCs (mean of age (m) = 13.18 years, 37% female) and their typically developing siblings (m = 12.9 years, 45% female) in combination with data from the European Centre for Disease Prevention and Control, the University of Oxford, and the Central Intelligence Agency (CIA) World Factbook, to create a multilevel data set. Using stepwise multilevel modelling, we generated child-, family- and country-related factors that may have contributed to the anxiety levels of children with NDCs, their siblings if they had any, and their parents. All data were reported by parents. Results: Our results suggest that parental anxiety was best explained by family-related factors such as concerns about COVID-19 and illness. Children's anxiety was best explained by child-related factors such as children's concerns about loss of routine, family conflict, and safety in general, as well as concerns about COVID-19. In addition, anxiety levels were linked to the presence of pre-existing anxiety conditions for both children with NDCs and their parents. Conclusions: The present study shows that across the globe there was a raise in anxiety levels for both parents and their children with NDCs because of COVID-19 and that country-level factors had little or no impact on explaining differences in this increase, once family and child factors were considered. Our findings also highlight that certain groups of children with NDCs were at higher risk for anxiety than others and had specific concerns. Together, these results show that anxiety of families and their children with NDCs during the COVID-19 pandemic were predicted by very specific concerns and worries which inform the development of future toolkits and policy. Future studies should investigate how country factors can play a protective role during future crises.

Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system.

The utility and safety of postmenopausal hormone replacement therapy has recently been put into question by large clinical trials. Their outcome has been extensively commented upon, but discussions have mainly been limited to the effects of estrogens. In fact, progestagens are generally only considered with respect to their usefulness in preventing estrogen stimulation of uterine hyperplasia and malignancy. In addition, various risks have been attributed to progestagens and their omission from hormone replacement therapy has been considered, but this may underestimate their potential benefits and therapeutic promises. A major reason for the controversial reputation of progestagens is that they are generally considered as a single class. Moreover, the term progesterone is often used as a generic one for the different types of both natural and synthetic progestagens. This is not appropriate because natural progesterone has properties very distinct from the synthetic progestins. Within the nervous system, the neuroprotective and promyelinating effects of progesterone are promising, not only for preventing but also for reversing age-dependent changes and dysfunctions. There is indeed strong evidence that the aging nervous system remains at least to some extent sensitive to these beneficial effects of progesterone. The actions of progesterone in peripheral target tissues including breast, blood vessels, and bones are less well understood, but there is evidence for the beneficial effects of progesterone. The variety of signaling mechanisms of progesterone offers exciting possibilities for the development of more selective, efficient, and safe progestagens. The recognition that progesterone is synthesized by neurons and glial cells requires a reevaluation of hormonal aging.

ARCHITECT® urine-neutrophil gelatinase-associated lipocalin (u-NGAL) assay as new prognostic marker for clear cell Renal Cell Carcinoma (ccRCC) (preliminary results).

INTRODUCTION: Biomarkers for the diagnosis and monitoring treatment response of kidney cancer are urgently needed. Neutrophil gelatinase-associated lipocalin (NGAL) is a relevant urinary biomarker for the diagnosis of a wide variety of acute and chronic kidney diseases. Its potential utility as a prognostic marker of kidney cancer is largely unknown and, therefore, was the subject of this investigation. MATERIALS AND METHODS: A retrospective study was done on 50 kidney tumor patients (urine samples prospectively collected before nephrectomy between 2004 and 2012, stored at Biobank Resource Center). The specificity, sensitivity and the predictive value of NGAL were determined for progression-free and disease-specific survival after nephrectomy in renal cell carcinoma (particularly, the clear cell renal cell carcinoma (ccRCC)). Urinary NGAL concentration (u-NGAL) was determined by CMIA technique (ARCHITECT® urine NGAL essay/ABBOTT®). RESULTS: Out of the 50 kidney tumor patients, 40 had clear cell carcinoma with a median u-NGAL excretion of 1.4 (IQR: 5.76) ng/mg urinary creatinine (Ucr). u-NGAL was correlated to tumor stage (p = 0.005), and Fuhrman grade (p = 0.0002). Multivariate Cox regression analysis showed a significant association between u-NGAL excretion and clear cell renal cell carcinoma progression free survival and disease specific survival (p = 0.002; p = 0.0001). CONCLUSIONS: Urinary NGAL was significantly associated with the stage and the grade of kidney cancer. u-NGAL excretion could be considered as a potential biomarker to identify ccRCC patients with the more pejorative outcomes.

Local synthesis and dual actions of progesterone in the nervous system: neuroprotection and myelination.

Progesterone (PROG) is synthesized in the brain, spinal cord and peripheral nerves. Its direct precursor pregnenolone is either derived from the circulation or from local de novo synthesis as cytochrome P450scc, which converts cholesterol to pregnenolone, is expressed in the nervous system. Pregnenolone is converted to PROG by 3beta-hydroxysteroid dehydrogenase (3beta-HSD). In situ hybridization studies have shown that this enzyme is expressed throughout the rat brain, spinal cord and dorsal root ganglia (DRG) mainly by neurons. Macroglial cells, including astrocytes, oligodendroglial cells and Schwann cells, also have the capacity to synthesize PROG, but expression and activity of 3beta-HSD in these cells are regulated by cellular interactions. Thus, Schwann cells convert pregnenolone to PROG in response to a neuronal signal. There is now strong evidence that P450scc and 3beta-HSD are expressed in the human nervous system, where PROG synthesis also takes place. Although there are only a few studies addressing the biological significance of PROG synthesis in the brain, the autocrine/paracrine actions of locally synthesized PROG are likely to play an important role in the viability of neurons and in the formation of myelin sheaths. The neuroprotective effects of PROG have recently been documented in a murine model of spinal cord motoneuron degeneration, the Wobbler mouse. The treatment of symptomatic Wobbler mice with PROG for 15 days attenuated the neuropathological changes in spinal motoneurons and had beneficial effects on muscle strength and the survival rate of the animals. PROG may exert its neuroprotective effects by regulating expression of specific genes in neurons and glial cells, which may become hormone-sensitive after injury. The promyelinating effects of PROG were first documented in the mouse sciatic nerve and in co-cultures of sensory neurons and Schwann cells. PROG also promotes myelination in the brain, as shown in vitro in explant cultures of cerebellar slices and in vivo in the cerebellar peduncle of aged rats after toxin-induced demyelination. Local synthesis of PROG in the brain and the neuroprotective and promyelinating effects of this neurosteroid offer interesting therapeutic possibilities for the prevention and treatment of neurodegenerative diseases, for accelerating regenerative processes and for preserving cognitive functions during aging.

Phytoremediation of petroleum hydrocarbons in tropical coastal soils. I. Selection of promising woody plants.

GOAL, SCOPE AND BACKGROUND: This glasshouse study is aimed at evaluating tropical plants for phytoremediation of petroleum hydrocarbon-contaminated saline sandy subsurface soils. Tropical plants were selected for their ability to tolerate high salinity and remove No. 2 diesel fuel in coastal topsoil prior to further investigation of the phytoremediation feasibility in deep contaminated soils. The residual petroleum-hydrocarbon contaminant at the John Rogers Tank Farm site, a former petroleum storage facility, at Hickam Air Force Base, Honolulu, Hawaii, is located in a coastal area. It lies below a layer of silt in the subsurface, in loamy sand characterized by moderate salinity and high pH. Little is known regarding the ability of tropical plants to remediate petroleum hydrocarbon-contaminated subsurface soil in Hawaiian and other Pacific Island ecosystems although suitable plants have been identified and utilized for bioremediation in surface soil or marine sediments. METHODS: The experiments were conducted in long narrow pots under glasshouse conditions in two phases. A preliminary experiment was done with nine tropical plants: kiawe (Prosopis pallida), milo (Thespesia populnea), common ironwood (Casuarina equisetifolia), kou (Cordia subcordata), tropical coral tree (Erythrina variegata), false sandalwood (Myoporum sandwicense), beach naupaka (Scaevola sericea), oleander (Nerium oleander), and buffelgrass (Cenchrus ciliaris). These plants were screened for resistance to high salinity treatment (2% NaCl) and two diesel fuel levels (5 and 10 g No. 2 diesel fuel/kg soil) in separate treatments. Plants that showed good tolerance of both factors were further evaluated in a second phase for their efficacy in the phytoremediation of diesel-fuel petroleum hydrocarbons under moderate salinity treatment (1% NaCl). RESULTS: Tropical coral tree and buffelgrass were susceptible to either 2% NaCl or diesel fuel at 10 g/kg soil, but tolerant of diesel fuel at 5 g/kg soil. Kiawe, milo, kou, common ironwood, N. oleander, beach naupaka and false sandalwood were tolerant of high salinity (2% NaCl) or high diesel fuel level (10 g/kg soil). These seven plants were also tolerant of the combined adverse effects of a moderate salinity (1% NaCl) and 10 g diesel fuel/kg soil. Three trees, kiawe, milo and kou significantly accelerated the degradation of petroleum hydrocarbons in the soil spiked with 10 g diesel fuel/kg soil under a moderate salinity treatment (1% NaCl). CONCLUSION: Thus the tropical woody plants, kiawe, milo and kou showed potential for use in phytoremediation of petroleum hydrocarbons in coastal tropical soils. RECOMMENDATIONS AND OUTLOOK: Two fast growing trees, milo and kou, appeared promising for further phytoremediation evaluation in experiments that simulate the soil profile at the field site.

Phytoremediation of petroleum hydrocarbons in tropical coastal soils. II. Microbial response to plant roots and contaminant.

GOAL, SCOPE AND BACKGROUND: The goal of this study was to understand the interaction between plants and microorganisms during petroleum-hydrocarbon bioremediation in Pacific Islands coastal soils. Total bacteria and hydrocarbon-degrading microorganisms population dyanamics were examined in the rhizospheres of tropical trees and shrubs, which were evaluated for their phytoremediation potential in a greenhouse experiment. The respective and combined effects of plant roots and diesel contaminant on the microbial populations were determined in relation to diesel fuel depletion. An increase in the grading populations size of the hydrocarbon-degrading populations of microbes, elicited by rhizodeposition, is generally regarded as conducive to an enhanced degradation of petroleum hydrocarbon pollutants in vegetated soil. METHODS: The soil was a coastal sandy loam (pH 7.8) which was artificially contaminated with 10 g of No. 2 diesel fuel/kg soil or left uncontaminated. The pots were irrigated with fertilizer and 1% NaCl. The enumerations were carried out in the contaminated and uncontaminated rhizospheres of three trees, kiawe (Prosopis pallida), milo (Thespesia populnea), and kou (Cordia subcordata) and three shrubs, beach naupaka (Scaevola sericea), false sandalwood (Myoporum sandwicense), and oleander (Nerium oleander). Unplanted control soils were included in the experiment. Total bacteria and phenanthrene-degrading bacteria were enumerated on plates. Diesel- and pristane-degrading microorganisms were enumerated by the most-probable-number technique in tissue-culture plates. RESULTS AND DISCUSSION: All four types of microorganisms responded to the rhizosphere of the 6 plants in uncontaminated soil and to the diesel contaminant in unplanted soil. In contaminated rhizospheres, no effect of the plant on the hydrocarbon-degrader numbers was visible. Total bacteria responded more to the plant roots than to the contaminant. The phenanthrene-degrading bacteria and pristane-degrading microorganisms were more influenced by the contaminant than by the plants. The diesel-degrading microorganisms were equally stimulated by the plants and the contaminant. The numbers of hydrocarbon degraders were similar in the contaminated rhizospheres of the three effective plants (kiawe, kou, and milo) and in those of the three ineffective shrubs. CONCLUSION: The results suggest the quality of the rhizodeposition is plant-dependent and governs the type of diesel-degrader populations that will be enhanced by a given plant. RECOMMENDATIONS AND OUTLOOK: In the proposed phytoremediation-benefit model plant roots maintain high levels of hydrocaron degraders in uncontaminated soil. When the root enters a contaminated zone of soil, those hydrocarbon degraders that prefer the contaminant would switch to the contaminant as a carbon source, effectively removing the hydrocarbons. If the root exudates and the contaminant are equally attractive to the hydrocarbon degraders, the contaminant degradaton would be less effective.

Lobectomy and postoperative thromboprophylaxis with enoxaparin improve blood hypercoagulability in patients with localized primary lung adenocarcinoma.

BACKGROUND: Patients with lung adenocarcinoma undergoing surgery are in high risk for VTE and receive routine post-operative thromboprophylaxis with LWMH. AIM: We investigated markers of hypercoagulability in patients with primary localized adenocarcinoma and the modifications induced by lobectomy and postoperative administration of enoxaparin. MATERIALS AND METHODS: Patients suffering from localised primary lung adenocarcinoma (n=15) scheduled for lobectomy were studied. The control group consisted of 15 healthy age and sex-matched individuals. Blood was collected before anaesthesia induction and after surgery, at several intervals until the 7th post-operative day. Samples were assessed for thrombin generation, phosphatidylserin expressing platelet derived microparticles expressing (Pd-MP/PS(+)), tissue factor activity (TFa), FVIIa and TFPI levels, procoagulant phospholipid dependent clotting time and anti-Xa activity. RESULTS: At baseline, patients showed increased thrombin generation and Pd-MP/PS(+). After lobectomy thrombin generation significantly decreased. Administration of enoxaparin attenuated thrombin generation. In about 50% of samples collected post-operatively an increase of thrombin generation occurred despite the presence of the expected anti-Xa activity in plasma. At the 7th post-operative day, 3 out of 15 patients showed a significant increase of thrombin generation. CONCLUSION: In patients with localized lung adenocarcinoma, hypercoagulability is characterized by high thrombin generation and increased concentration of Pd-MP/PS(+). Tumor mass resection is related with attenuation of thrombin generation, which is inhibited by postoperative thromboprophylaxis with enoxaparin. The response to enoxaparin is not predicted by the concentration of the anti-Xa activity in plasma. The assessment of thrombin generation during prophylaxis with enoxaparin allows to identify patients with high residual plasma hypercoagulability.

Interactions among buffelgrass, phenanthrene and phenanthrene-degrading bacteria in gnotobiotic microcosms.

An experiment was undertaken in gnotobiotic microcosms to determine the role of buffelgrass (Cenchrus ciliaris) and a phenanthrene-degrading bacterium (strain PM600) in the degradation of phenanthrene. The Gram-negative bacterium was identified as a Sphingomonas sp. by 16S rRNA gene sequence analysis and as S. paucimobilis by biochemical tests (API 20 NE strips). Its yellow pigment corresponded to nostoxanthin and its cellular fatty acids were typical of the genus Sphingomonas. Moreover, it was devoid of lipopolysaccharides. Strain PM600 was tested for growth on mineral medium supplemented with No. 2 diesel, hexadecane, mineral oil, pristane, phenanthrene, and pyrene as single carbon sources. It was capable of utilizing phenanthrene only. In the gnotobiotic microcosms silica sand was either or not supplemented with 150 mg of phenanthrene kg(-1) sand, inoculated with strain PM600, and planted to sterile young seedlings of buffelgrass. After 28 days, 67% of the reduction of the phenanthrene concentration was assigned to degradation by the bacterium and ca. 20% to abiotic factors. No statistically significant effect of the young buffelgrass was found. In the absence of phenanthrene, the bacterial population significantly increased in the rhizosphere of buffelgrass. However, in the presence of buffelgrass and phenanthrene, the bacterial population preferentially responded to phenanthrene. The growth of buffelgrass was severely curtailed by phenanthrene in the absence of the bacterium. However, strain PM600 effectively protected buffelgrass against the phytotoxicity of phenanthrene.

[Multidisciplinary management of gastroplasty candidates: example of Avicenne Hospital]. / Parcours multidisciplinaire du candidat à une gastroplastie: l'exemple de l'hôpital Avicenne.

The decision to perform gastroplasty must be made by a multidisciplinary team. This organization ensures compliance with good practice guidelines. Multidisciplinary management after surgery is also essential but patients' adhesion to follow-up is relatively poor.

Reticulated platelets: a reliable measure to reduce prophylactic platelet transfusions after intensive chemotherapy.

BACKGROUND: Reticulated platelets (RPs) are the youngest circulating platelets (PLTs). The aim of our study was to predict PLT recovery with RP percentage (RP%) and therefore to identify PLT transfusions that could be avoided after autologous peripheral blood progenitor cell (PBPC) transplantation. STUDY DESIGN AND METHODS: With a whole-blood dual-labeling flow cytometric method, RP% was prospectively assessed in 47 patients who received myeloablative chemotherapy followed by autologous PBPC transplantation. Retrospective analysis of RP evolution identified three time points: nadir of the RP% (NRP), imminent PLT recovery (IPR) corresponding to an RP% of greater than 7 percent, and PLT transfusion autonomy (PTA). RESULTS: Median occurrences of NRP, IPR, and PTA were on Days +5, +8, and +12 after transplantation, respectively. The RP% value at NRP (4%) was significantly lower compared to the IPR (15%) and PTA (14%). Thirty patients (64%) achieved PTA within 4 days after IPR. On Day +8, if RP% was greater than 7 percent, positive and negative predictive values for PTA within 4 days, specificity, and sensitivity were 79, 63, 66, and 76 percent, respectively. Fever between IPR and PTA was the only factor found to negatively influence PLT recovery (p = 0.02). All patients required at least one PLT transfusion. Among patients with rapid PLT recovery (IPR-PTA interval < 4 days; n = 30), half of them received one PLT transfusion after RP increase, which could be avoided. CONCLUSION: These encouraging results may allow us to reduce the prophylactic PLT transfusion according to patients RP% increase.

Evaluation of agriculture-based phytoremediation in Pacific island ecosystems using trisector planters.

It is difficult to directly evaluate the efficacy of phytoremediation of petroleum hydrocarbon contaminants embedded in deep soil layers, especially if the contaminants are of relatively low concentration and are unevenly distributed. This report describes the greenhouse and laboratory experiments carried out to evaluate a field demonstration project. A trisector planter was designed to simulate field conditions, including soil profiles and field management of the trees selected. The third or bottom section of the planter was spiked with known quantities of 6 diesel-fuel components and the reduction of their concentrations was monitored after 200 days under the influence of the plant root systems. Results are statistically compared; among the three tree species used, milo (Thespesia populnea) and kou (Cordia subcordata) are more effective than false sandalwood (Myoporum sandwicense) in reducing the concentration of the spiked contaminant. Enumerations of populations of hydrocarbon-degrading microoorganisms in the bottom section suggest that biodegradation may be affected by the response of microorganisms to both the "close rhizosphere" (soil within 1 mm of the root) and the "expanded rhizosphere" (soil in the bottom section after root removal). Root exudates leached from the upper sections could be responsible for the expanded rhizosphere effect in the bottom section.

In vitro aspirin resistance detected by PFA-100 closure time: pivotal role of plasma von Willebrand factor.

The in vitro closure time (CT), determined by the Platelet Function Analyzer (PFA-100), is used to monitor patients treated with aspirin. A relatively high percentage of in vitro aspirin resistance was reported despite an adequate inhibition of platelet response to arachidonic acid and we investigated whether high plasma levels of von Willebrand factor ristocetin cofactor activity (vWF:RCo) may contribute to this profile. Platelet aggregation test, CT [collagen adrenaline (CEPI-CT) and collagen adenosine 5'-diphosphate (ADP) (CADP-CT)], and vWF:RCo levels were evaluated in 55 consecutive patients receiving aspirin (75-250 mg/d) versus 32 untreated control subjects. All the aspirin-treated patients showed platelet aggregation responses that reflected the aspirin intake. However, CT data analysis enabled aspirin good-responder (GR) and aspirin bad-responder (BR) patients to be identified. All GR group subjects (n = 27), had a CEPI-CT and a CADP-CT longer than 300 s and 96 s respectively. The BR group (n = 28) had CEPI-CT values below 200 s and all CADP-CT were in the normal range (77 +/- 19 s). Interestingly, the BR plasma vWF:RCo levels were significantly higher (159 +/- 43%) than those of the GR group (121 +/- 34%) (P < 0.01), which were similar to control values (114 +/- 31%). A negative correlation between vWF:RCo and CT values was established. We demonstrate that in vitro aspirin-resistance, revealed by PFA-100 CT prolongation failure, is correlated to increased plasmatic vWF:RCo levels, reinforcing its particular importance in PFA-100 cartridges performance.